About

Paola Arlotta is a Professor of Stem Cell and Regenerative Biology at Harvard University within the Department of Molecular and Cellular Biology. Her work primarily aims at defining the molecular rules that shape and retain neuronal diversity in the cerebral cortex. She investigates how pyramidal neuron diversity influences the behavior of other neurons and glia to build functional cortical circuits. Her research also explores the boundaries of postmitotic neuron identity stability in vivo. Additionally, her lab is interested in understanding and modeling complex human cortical pathology, focusing on developing new high-throughput in vitro models of human cortical development and neurodevelopmental disease using 3D cerebral organoids.

Research topics

• Computer Science
• Biology
• Neuroscience
• Computational biology
• Genetics
• Artificial Intelligence
• Zoology
• Psychology
• Evolutionary biology

Selected publications

• Domínguez-Iturza, N., Jokhi, V., Kim, K., et al., Developmental Cell 2026 - Mendeley Data Figures

  Mendeley Data · 2026-05-08

  datasetOpen accessSenior author

  Additional data figures for Domínguez-Iturza, Jokhi, Kim et al., (2026). Molecular cues from distinct neuron classes drive differential myelination in the neocortex. Developmental Cell The PDF includes 6 supplemental figures: Mendeley Data Figure 1. Cell sorting and quality control analysis of scRNA-seq of oligodendrocytes from Plp1-EGFP+/- micro-dissected cortical layers, related to Figure 1. Mendeley Data Figure 2. MOL states across time and cortical layers, related to Figure 1. Mendeley Data Figure 3. Developmental trajectory analysis of oligodendrocyte subsets, related to Figure 1. Mendeley Data Figure 4. Analysis of scRNA-sequencing datasets from mouse somatosensory cortex at P7 and P21, related to Figure 3. Mendeley Data Figure 5. Analysis of neuronal and oligodendrocyte populations in scRNA-sequencing data from mouse somatosensory cortex, related to Figure 3. Mendeley Data Figure 6. Axonal caliber is unaffected after overexpression or silencing of Ncam1 and Fgf18, related to Figure 5, 6 and 7.

  PublisherDOI

• Comprehensive single cell profiling of ageing glial cells reveals impaired Wnt signalling and Jun transcription factors regulating cortical astrocytes

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-04-17

  article

  Abstract Understanding age-related cellular dysfunction in the brain is essential for developing strategies to promote healthy ageing. Towards this aim, we took advantage of a previously established mild dissociation method to profile cells in the cerebral cortex grey matter of adult and aged mice. This revealed glial cells with largely up-regulated and other glia and neurons with largely down-regulated gene expression upon ageing. Astrocytes were involved in increased interactions with microglia and decreased interaction with neurons, high-lighting potent age-induced changes in their regulatory roles. Single cell RNA-seq and single nuclei multiome analysis of astrocytes uncovered down-regulation of Wnt-signalling with increased expression of its inhibitors and reduced RNA and protein levels of its effectors JunB/D, acting downstream of Wnt signalling in ageing. This was confirmed by RNA-scope and immunostainings, as well as in human data. Notably, injection of JunD-expressing viral vectors in astrocytes increased their proliferation and HMGB1 levels in the aged brain, indicative of a more youthful astrocyte state. Main points Transcriptomic analysis uncovers cell type–specific impact of ageing in the cortical grey matter, including altered intercellular communication networks. Multiomic profiling identifies dysregulated Wnt signalling in ageing cortical astrocytes. Ageing astrocytes exhibit upregulation of the Wnt signalling regulators Maml2 and Daam2, accompanied by downregulation of the AP-1 transcriptional complex component JunD. Overexpression of JunD increases proliferation after mild injury in aged astrocytes.

  PublisherDOI

• Domínguez-Iturza, N., Jokhi, V., Kim, K., et al., Developmental Cell 2026 - Mendeley Data Figures

  Mendeley Data · 2026-05-08

  datasetOpen accessSenior author

  Additional data figures for Domínguez-Iturza, Jokhi, Kim et al., (2026). Molecular cues from distinct neuron classes drive differential myelination in the neocortex. Developmental Cell The PDF includes 6 supplemental figures: Mendeley Data Figure 1. Cell sorting and quality control analysis of scRNA-seq of oligodendrocytes from Plp1-EGFP+/- micro-dissected cortical layers, related to Figure 1. Mendeley Data Figure 2. MOL states across time and cortical layers, related to Figure 1. Mendeley Data Figure 3. Developmental trajectory analysis of oligodendrocyte subsets, related to Figure 1. Mendeley Data Figure 4. Analysis of scRNA-sequencing datasets from mouse somatosensory cortex at P7 and P21, related to Figure 3. Mendeley Data Figure 5. Analysis of neuronal and oligodendrocyte populations in scRNA-sequencing data from mouse somatosensory cortex, related to Figure 3. Mendeley Data Figure 6. Axonal caliber is unaffected after overexpression or silencing of Ncam1 and Fgf18, related to Figure 5, 6 and 7.

  PublisherDOI

• Cell-state mapping reveals a reversible neuroblast accumulation in the aging mouse hippocampus

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-04-27

  articleOpen access

  Hippocampal neurogenesis supports learning and memory by generating new granule cells throughout life. However, both the rate and speed of this process decline with age. To elucidate the molecular determinants underlying the effects of aging on neuronal differentiation, we combined lineage tracing of adult-born granule cells (aGCs) with single-nucleus RNA sequencing. This approach produced a temporally resolved transcriptional atlas of aGC development. Aging led to a marked accumulation of postmitotic neuroblasts (NBs), revealing a stage-specific bottleneck in the neurogenic trajectory. Voluntary running reduced NB accumulation by restoring the progression through this developmental impasse, allowing neuronal maturation to be resumed. Notably, this effect involved a significant reduction of apoptosis at the NB stage. Together, these findings identify a reversible apoptotic checkpoint that contributes to age-related neurogenic decline and highlight postmitotic NBs as a key regulatory cell state capable of integrating pro-maturational signals to control the neurogenic output.

  PublisherDOI

• The need for a global effort to attend to human neural organoid and assembloid research

  Science · 2025-11-06 · 4 citations

  article

  A continuing international process is needed to monitor and advise this rapidly progressing field.

  PublisherDOI

• Supplementary Table S3 from Glioblastoma Cortical Organoids Recapitulate Cell-State Heterogeneity and Intercellular Transfer

  2025-02-07

  supplementary-materialsOpen access

  <p>Supplementary Table S3 shows gene sets defining malignant programs in human GCOs.</p>

  PublisherDOI

• Advances, challenges, and opportunities of human midbrain organoids for modelling of the dopaminergic system

  The EMBO Journal · 2025-07-02 · 8 citations

  reviewOpen access

  Dopaminergic neurons in the ventral midbrain are critical for regulating movement, cognition, and emotion. Ventral midbrain organoids can be used to model both development and diseases of the dopaminergic system, especially Parkinson's disease. Here, we summarize recent advances and remaining challenges in developing such three-dimensional organoids from human pluripotent stem cells. We outline how ventral midbrain organoid systems have progressed from early three-dimensional culture models to sophisticated, engineered, multiregional systems that more accurately replicate the complex network of dopaminergic neurons. Furthermore, we examine how the development of organoid models from other brain regions, particularly the forebrain, provides complementary insights that can accelerate progress also in the field of midbrain organoids, towards the generation of more advanced in vitro systems for midbrain dopaminergic neurons and their circuitry. Such cutting-edge human stem cell-based models offer powerful platforms for investigating dopaminergic neuron generation, function, and connectivity, thereby enhancing disease modelling, drug discovery, and the development of targeted cell-based therapies.

  PublisherOA PDFDOI

• Data from Glioblastoma Cortical Organoids Recapitulate Cell-State Heterogeneity and Intercellular Transfer

  2025-02-07 · 1 citations

  preprintOpen access

  <div>Abstract<p>Glioblastoma (GBM) is characterized by heterogeneous malignant cells that are functionally integrated within the neuroglial microenvironment. In this study, we model this ecosystem by growing GBM into long-term cultured human cortical organoids that contain the major neuroglial cell types found in the cerebral cortex. Single-cell RNA sequencing analysis suggests that, compared with matched gliomasphere models, GBM cortical organoids more faithfully recapitulate the diversity and expression programs of malignant cell states found in patient tumors. Additionally, we observe widespread transfer of GBM transcripts and GFP to nonmalignant cells in the organoids. Mechanistically, this transfer involves extracellular vesicles and is biased toward defined GBM cell states and astroglia cell types. These results extend previous GBM organoid modeling efforts and suggest widespread intercellular transfer in the GBM neuroglial microenvironment.</p><p><b>Significance:</b> Models that recapitulate intercellular communications in GBM are limited. In this study, we leverage GBM cortical organoids to characterize widespread mRNA and GFP transfer from malignant to nonmalignant cells in the GBM neuroglial microenvironment. This transfer involves extracellular vesicles, may contribute to reprogramming the microenvironment, and may extend to other cancer types.</p><p><a href="https://aacrjournals.org/cancerdiscovery/article/doi/10.1158/2159-8290.CD-24-1661" target="_blank"><i>See related commentary by Shakya et al., p. 261</i></a></p></div>

  PublisherDOI

• Brain Organoids: Tools for Understanding the Uniqueness and Individual Variability of the Human Brain

  Annual Review of Genomics and Human Genetics · 2025-08-25 · 5 citations

  reviewOpen accessSenior author

  Understanding the drivers of human brain specialization, and how specialized properties are codified during development and evolution, seems to be within reach for the first time. Improved cell-based experimental models of the human brain have empowered the field to address some of the most fundamental questions about our brains, including mechanisms of neurodevelopment, the etiology of neurological disease, and the underpinnings of human-to-human variation in brain function and response. The emergence of scalable in vitro systems has enabled investigation of interindividual variation within large human cohorts in both normal development and disease processes, which is fundamental to developing effective and personalized treatments. This review explores recent advancements in organoid technology, highlighting future directions that employ interdisciplinary approaches to enhance the physiological relevance of these models. This work promises to bring us ever closer to understanding not only what makes a brain human but also how each of our brains is human in unique ways.

  PublisherDOI

• Supplementary Figure S5 from Glioblastoma Cortical Organoids Recapitulate Cell-State Heterogeneity and Intercellular Transfer

  2025-02-07

  preprintOpen access

  <p>Supplementary Figure S5 describes extracellular vesicle mediated intercellular transfer in GCOs, related to Figure 5.</p>

  PublisherDOI

Recent grants

• Novel epigenetic mechanisms in neuronal development and cognitive function

  NIH · $6.1M · 2012–2023

• High throughput assaying of circuit activity and connectivity in brain organoids

  NIH · $2.5M · 2020–2024

• Genetic targeting of cortical pyramidal neuron subtypes

  NIH · $3.9M · 2013–2018

• Molecular principles of neuronal maturation and integration in the adult and aging brain

  NIH · $2.7M · 2018–2024

• Developmental origins of mental illness: evolution and reversibility

  NIH · $38.3M · 2011–2024

Frequent coauthors

• Jeffrey D. Macklis

  Harvard University Press

  81 shared

• Bradley J. Molyneaux

  Brigham and Women's Hospital

  57 shared

• Xin Jin

  Broad Institute

  50 shared

• Aviv Regev

  Broad Institute

  48 shared

• Simona Lodato

  Humanitas University

  45 shared

• Kwanho Kim

  Harvard University

  43 shared

• Silvia Velasco

  University of Melbourne

  39 shared

• Juliana Brown

  Harvard University

  35 shared

Labs

• Arlotta LabPI